[unreadable] Morphine is the drug of choice for the management of severe pain due to its central actions at mu opioid receptors. With repeated administration, patients become tolerant to the analgesic effects. Tolerance to peripheral opioid receptors develops more slowly, resulting in differential tolerance and an exacerbated constipatory effect. It is hypothesized that efflux transporters at the Blood-Brain Barrier play a role in the development of differential tolerance. P-glycoprotein (P-gp) is up regulated in morphine tolerant animals and morphine is a P-gp substrate. Therefore, the design of opioids with decreased activity as P-gp substrates will result in analgesics with reduced constipation. The removal of 3-phenol groups in 4,5-epoxymorphinans is hypothesized to decrease P-gp affinity and is known to reduce potency at opioid receptors. The highly potent mu agonist etorphine has similar P-gp substrate affinity to morphine. Replacement of the 3-phenol of etorphine will therefore reduce P-gp substrate activity and bring opioid potency to a therapeutic level in humans. Replacements at the 20-position will refine potency of the resulting weak P-gp substrates. The long-term goal is to develop novel therapeutics for the treatment of chronic, severe pain. [unreadable] [unreadable] [unreadable] [unreadable]